Method of treating depression with certain diazepinoindoles and anti-depressant compositions thereof

ABSTRACT

THE ANTI-DEPRESENT ACTIVITY OF 2,3,4,5-TETRAHYDRO-1H1,,4-DIAZEPION(1,2-A)INDOLES, INCLUDING THOSE SUBSTITUTED IN THE 9-POSITION WITH HALO OR LOWER ALKOXY, AND IN THE 11POSITION WITH LOWER ALKYL.

3,787,577 METHOD OF TREATING DEPRESSION WITH CER- TAIN DIAZEPINOINDOLESAND ANTI-DEPRES- SANT COMPOSITIONS THEREOF Joseph Francis Gardocki,Doylestown, Pa., assignor to McNeil Laboratories, Inc. No Drawing. FiledSept. 30, 1971, Ser. No. 185,361 Int. Cl. A61k 27/00 U.S. Cl. 424-274 12Claims ABSTRACT OF THE DISCLOSURE The anti-depressant activity of2,3,4,5-tetrahydro-1I-I- l,4-diazepino[l,2-a]indoles, including thosesubstituted in the 9-position with halo or lower alkoxy, and in the 11-position with lower alkyl.

The invention relates to the use of certain2,3,4,5-tetrahydro-1H-1,4-diazepino[l,2-a]indoles as antidepressantagents and to pharmaceutical compositions thereof, preferably in dosageunit form. The particular diazepinoindoles so utilized may berepresented by the following structural formula:

R T R in base form or in the form of a therapeutically activeacid-addition salt, wherein R is a member selected from the groupconsisting of hydrogen, halo, preferably chloro, and lower alkoxy,preferably methoxy; and R is a member selected from the group consistingof hydrogen and lower alkyl, preferably methyl. Typical acid-additionsalts are those formed by reacting the base (I) with an equivalent of apharmacologically-acceptable acid such as, for example, hydrochloric,hydrobromic, sulfuric, nitric, phosphoric, fumaric, benzoic, acetic,lactic, hexamic, benzene sulfonic and the like acids.

As used herein, the terms lower alkyl and lower alkoxy contain from 1 toabout 6 carbon atoms and may be straight or branched chained; and theterm halo denotes chloro, fluoro and bromo.

The subject diazepinoindoles (I) and their process of preparation aredescribed in Chemical Abstracts, 72, 55528v (1970), which refers to Ger.Otfen. 1,928,726.

It has now been found that the subject diazepinoindoles possess markedanti-depressant activity which appears to be mediated through an effecton the central nervous system (CNS) similar to two well-known clinicallyeffective anti-depressants, imipramine and iprindole, and are thereforeuseful in the treatment of depression when administered to depressedsubjects. The anti-depressant activity of these compounds has beenobserved in experimental animals, as demonstrated in two tests gen--United States Patent 3,787,577 Patented Jan. 22, 1974 erally acceptedin the study of anti-depressant activity of compounds in mice:

Test I: Clinically effective anti-depressants are known to antagonizethe effects of reserpine and reserpine-like compounds (i.e.,tetrabenazine) in laboratory animals. Imipramine has been reported toeffect a rise in body temperature when administered to hypothermicreserpinized mice. The reversal of reserpin hypothermia in mice has beenproposed as a method for the screening of antidepressant activity(Askew, B. M., Life Sci., 10, 725, 1963).

Test II: The antagonism of the decrease in exploratory activity andptosis, induced by tetrabenazine in mice, has been employed as anexperimental model of depression for the study of the anti-depressantactivity of imipramine and amitriptyline [Vernier, V. G., Hanson, M. H.,and Stone, C. A., 1962, in Psychosomatic Medicine, eds. I. H. Nodine andJ. H. Moyer (Lea and Febiger, Philadelphia) p. 683].

The subject diazepinoindoles, when studied with respect to their eifecton reserpine hypothermia in mice and on the decrease in exploratoryactivity and ptosis induced with tetrabenazine in mice, shows positiveanti-depressant activity. In the following test procedures, theanti-depressant activity of four compounds of Formula I is demonstrated,it being understood that such compounds are not set forth for purposesof limiting the invention thereto, but only to exemplify the usefulantidepressant properties of all the compounds within the scope ofFormula I, including the pharmaceutically acceptable acid-addition saltsthereof.

The reserpine hypothermia assay is conducted according to the method ofAskew (cited above) with the following modifications: (a) the dose ofreserpine employed is 5 mg./ kg. rather than 2 mg./kg.; (b) theesophogeal temperature is taken rather than the rectal temperature.Thus, the modified procedure is as follows: mice are injected with 5mg./kg. s.c. of reserpine 17-18 hours prior to the initiation of theinjection of the test compound. Immediatey prior to the intraperitonealinjection of the test compound, the esophogeal temperature is recorded,for example, by using a thermocouple and an electric universalthermometer type TE3. The esophogeal temperature is again recorded atone, two and three hours following the injection of the test compound. Agroup of 10 male albino mice of the Swiss Webster strain, weighing from18-24 grams, are used per dosage level of the test compound. A group of10 reserpinized mice, injected with 10 ml./kg. of saline serve ascontrols. Two clinically effective anti-depressants, imipramine andiprindole, serve as reference standards. The room temperature is 23:1 C.The statistical significance of the difference between the mean bodytemperature at Zero time and at one, two and three hours respectively,is determined using the Students t Test. A value of P O.05 is taken assignificant.

The data presented in Table I, comparing four of the subjectdiazepinoindoles with the reference standards, show that the subjectdiazepinoindoles significantly elevate the body temperature inhypothermic reserpinized mice as do the reference anti-depressants,imipramine and iprindole.

TABLE I.EFFECT OF DIAZEPINOINDOLES. IMIPRAll/[INE AND IPRIN- DOLE INRESERPINE HYPOTHERMIA IN MICE Body temperature, C.

Compound Dose, i.p. hour 1 hour 2 hours 3 hours A 40 mg.lkg----. 27.d=1. 8 30. 95:2. 58 32. 75:1. 48 32. 05:1. 08 Saline. l0 mL/kg 27. Gil.2 26 9&1. 4 26 9:);1. 9 26. 7il. 3 B 40 rug/kg"-.- 32. 1:1;1. 98 mlJkg29. 7 i1. 7 60 mgJkg 30. did. 5B 10 mlJkg. 29. Oil. 1 80 mgJkg 28. 53:1.58 10 (kg. fidzO. 26.4 mg kg- 33 2=l=l. 4S Saline 10 26. 7*. 8 IprindoleHOL- 60 mg lkg--..- 30. 75:1. 88 Saline- 10 ml 27. diLO 1 Dose expressedin terms of the base form of the compound. :{Esophogeal temperature.

ora:

Compound A=2,3,4,5-tetrahydro-lH-1,4-diazepino[1,2-a]indole H01.-

Compound B=2,8,4,5-tetrahydro-Q-methoxy-lH-l, l-diazepinofl,2a]indoleHCl. CompoundC=9-chloro-2,3,4=,5-tetral1ydro-1H-1,4'diazepinoIl,2a]indole H01.goxproiongll)=9-chloro-2,3,4,5-tetrahydro-1l-methyl-lH-l,4'diazepino[1,2'a]indoleH01.

The effect of the subject diazepinoindoles on the deof imipramine andiprindole as shown by their elfect on crease in exploratory activity andptosis induced with reserpine hypothermia. in mice and on the decreasein tetrabcnazine in mice is demonstrated by the method of exploratoryactivity and ptosis induced with tetrabena- Vernier, V.G., et al. (citedabove). The mice employed zine in mice. The absence of overt stimulantactivity in are similar in body weight, sex and strain, as the mice miceis a further indication of the similarity of these didescribed used inthe reserpin hypothermia assay. azepinoindoles to that of imipramine andiprindole.

Mice are injected with the test compound minutes The anti-depressantactivity observed with the subject prior to the injection of 32 mg./kg.i.p. of tetrabenazine. diazepinoindoles is an unexpected and surprisingeffect Thirty minutes post tetrabenazine, the mice are tested for inview of the fact that the previously reported pharmathe presence ofnormal exploratory activity and ptosis. A cological properties of saiddiazepinoindoles (see previgroup of 10 mice injected with 32 mgjkg. i.p.serve as 30 ously cited literature reference) related to pulmonarycontrols. Three to live dosage levels, 10 mice per dosage vasodilationwhich would not suggest anti-depressant aclevel, are used per compound.The dose of the test comtivity.

pound that would be expected to antagonize (i.e., to re- To prepare thepharmaceutical compositions of this vert to normal as compared tountreated mice) the aforeinvention, a diazepinoindole of Formula I, inbase or acidmentioned efiects of tetrabenazine in 50% of mice so 35addition salt form, as the active ingredient is combined tested, ED and95% confidence limits, are calculated in intimate admixture with apharmaceutically acceptable according to the method of Litchfield, J. T.and Wilcoxon, carrier, which carrier may take a wide variety of forms F.(J. Pharmacol. Exptl. Therap. 96, 99, 1949). When depending on the formof preparation desired for adthe response to tetrabenazine in thecontrol group is 90% ministration. For example, in preparing thecompositions or less, a correction is made for natural mortality usingin oral dosage form, any of the usual pharmaceutical Abbotts formula(Finney, D. 1., 1964, Probit Analysis, media may be employed, such as,for example, water, glysecond edition, University Press, Cambridge, p.88). cols, oils, alcohols and the like in the case of oral liquid Asshown in Table II, the diazepinoindole compounds, preparations such assuspensions, elixirs and solutions; or as well as imipramine andiprindole, are efiective in resolid carriers such as starches, sugars,kaolin, lubricants, versing the decrease in exploratory activity andptosis inbinders, distintegrating agents and the like in the case ofduced with tetrabenazine in mice. powders, capsules and tablets. Becauseof their case in TABLE II.-EFFECT OF DLAZEPINOINDOLES IMIPRAMINE ANDIPRIN- DOLE ON TETRABENAZINE-INDUCED LOS OF EXPLORATORY ACTIVITY ANDPTOSIS IN MICE No. of Exploratory activity, dosage 85% confidencePtosis, ED" (95% D T 5 80.0 (41-152) mgJkg. 110.0 (75-161) mgJkgImipramine HO 1.1 (.71-L8) mgJkg. i.p 77 (.60-L0) rug/kg. i.p. IprindoleH01--- 130 (72-234) mgJkg. i.p-. 66.0 (53-82) mgJkg. i.p.

1 For identity of Compound, see Table I. I 10 mice used per dosage leveDose expressed in toms of the base form of the compound.

In addition to the two foregoing tests, the behavioral administration,tablets and capsules represent the most profile observed with thesubject diazepinoindoles, tested advantageous oral dosage form, in whichcase solid at doses of 3, 10, 30, 100 and 300 mg./ kg. i.p., in groupspharmaceutical carriers are obviously employed. For parof 3 mice each,in a standard mouse behavior assay, inenteral compositions, the carrierwill usually comprise dicates that the subject compounds do not produceovert sterile water, at least in large part, though otheringredistimulation in mice as does, for example, amphetamine. ents, forexample, to aid solubility, may be included. In- The behavioral profileone observes with imipramine and jectable solutions, for example, may beprepared in which iprindole under similar test conidtions also does notinthe carrier comprises saline solution, glucose solution or dicateovert stimulant activity as is seen with ampheta mixture of saline andglucose solution. Injectable susamine. pensions may also be prepared inwhich case appropri- From the foregoing, it is evident that the subjectdiazeate liquid carriers, suspending agents and the like may bepinoindoles possess anti-depressant activity similar to that employed.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for easeofadministration and uniformity of dosage. Dosage unit form as used inthe specification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets, capsules,pills, powder packets, wafers, injections, teaspoonfuls, tablespoonfulsand the like, and segregated multiples thereof. The amount of activeingredient per dosage unit will be from about 5 mg. to about 250 mg.,and, preferably, from about 25 mg. to about 150 mg.

The following formulations exemplify typical oral and parenteralanti-depressant pharmaceutical compositions in dosage unit form suitablefor administration to depressed subjects in accordance with the instantinvention.

Capsules: 10,000 hard gelatin capsules, each containing as the activeingredient (A1.) 25 milligram of 2,3,4,5-tetrahydro-lH-1,4-diazepino[1,2 a] indole hydrochloride are preparedfrom the following formulation:

Grams A1. 250 Lactose 750 Starch 25 Talc 250 Calcium stearate 10 Auniform mixture of the active and supplementary ingredients is preparedand filled into two-piece hard gelatin capsules.

Tablets: 5,000 compressed tablets, each containing as the activeingredient 10 milligrams of 2,3,4,5-tetrahydro-9-methoxy-lH-l,4-diazepino[1,2 a]indole hydrochloride are prepared fromthe following formulation:

Grams Al. 50 Starch 75 Dibasic calcium phosphate hydrous 500 Calciumstearate 2.5

The finely powdered ingredients are mixed well and granulated with 10%starch paste. The granulation is dried and compressed into tablets usingstarch as a disintegrant and calcium stearate as a lubricant.

Oral suspension: The following formulation provides liters of an oralsuspension comprising 25 mg. of9-chloro-2,3,4,5-tetrahydro-1H-1,4-diazepino[1,2-a]indole as the activeingredient per teaspoonful (5 mils):

Filtered purified water, p.s., ad. 5 liters.

Dissolve the parabens in the propylene glycol and add this solution to asolution of the sodium cyclamate, sodium saccharin and sucrose in halfthe water. Suspend the bentonite in hot (about 85 C.) water and stir for60 minutes. Add the bentonite solution to the former solution.

Dissolve the sulfosuccinate in some water and suspend the Al. in theresulting solution. Add the Antifoam A.F. Emulsion which has beendiluted to a lotion consistency with a minimum amount of water and mixwell.

Add the latter suspension of Al. to the former mixture and mix well. Addthe FD&C Yellow #5 dissolved in a Grams A.I. 5.0 Polysorbate 2.0 Sodiumchloride 9.0

Sodium carboxymethyl cellulose 10.0 Methyl paraben 1.8 Propyl paraben0.2 Water for injection, U.S.P., q.s. ad. 1 liter.

Dissolve the parabens, sodium chloride and carboxymethyl cellulose in /2the total volume of water by heating to C. to obtain a clear solution.Filter and autoclave. Dissolve the polysorbate in /3 the total volume ofwater. Filter and autoclave this second solution. Add sterile Al. to thesecond solution and pass through a sterile colloid mill. To theresulting suspension, add the first solution with uniform stirring. Q.s.with water and stir while filling into sterile vials.

The process of this invention comprises internally administering todepressed subjects an effective anti-depressant amount ofdiazepinoindole of Formula I or a therapeutically active acid-additionsalt thereof intimately admixed with a pharmaceutically acceptablecarrier. Pref, erably, the dosage per kilo of body weight of the subjecttreated would vary from about 1 mg. to about 80 mg. of the activeanti-depressant ingredient. The process also embraces the administrationof the hereinabove described dosage unit forms to such subjects foranti-depressant purposes. The preferred diazepinoindole is2,3,4,5-tetrahydro 1H 1,4 diazepino[1,2-a]indole and the therapeuticallyactive acid-addition salts thereof, most preferably, the hydrochloride.

What is claimed is:

1. The method of inhibiting depression which comprises intemallyadministering to a depressed subject a pharmaceutical compositioncomprising an effective antidepressant amount of a member selected fromthe group consisting of a diazepinoindole having the formula:

and the therapeutically active acid-addition salts thereof, wherein R isa member selected from the group consisting of hydrogen, halo and loweralkoxy, said halo being a member selected from the group consisting ofchloro, fluoro and bromo, and R is a member selected from the groupconsisting of hydrogen and lower alkyl, as an active ingredient inadmixture with a pharmaceutical carrier.

2. The method of claim 1 wherein said active ingredient is 2,3,4,5tetrahydro 1H l,4-diazepino[1,2-a] indole hydrochloride.

3. The method of claim 1 wherein said active ingredient is 2,3,4,5tetrahydro 9 methoxy 1H-l,4-diazepino[ l,2-a]indole hydrochloride.

4. The method of claim 1 wherein said active ingredient is 9 chloro2,3,4 tetrahydro l-H-1,4-diazepino- 1,2-a]indole hydrochloride.

5. The method of claim 1 wherein said active ingredient is 9 chloro2,3,4,5 tetrahydro-l1-methyl-lH-l,4- diazepino[ l,2-a]indolehydrochloride.

6. An anti-depressant pharmaceutical composition in dosage unit fromabout 5 to about 250 mg. of a member selected from the group consistingof a diazepinoindole having the formula:

R im

and the therapeutically active acid-addition salts thereof, wherein R isa member selected from the group consisting of hydrogen, halo and loweralkoxy, said halo being a member selected from the group consisting ofchloro, fluoro and bromo, and R is a member selected from the groupconsisting of hydrogen and lower alkyl, as an active ingredient inadmixture with a solid pharmaceutical carrier suitable for oraladministration.

7. Claim 6 wherein said active ingredient is 2,3,4,5-

8 tetrahydro 1H 1,4 diazepino[l,2-a]indole hydrochloride.

8. Claim 6 wherein said active ingredient is 2,3,4,5- tetrahydro 9methoxy 1H 1,4diazepino[l,2-a] indole hydrochloride.

9. Claim 6 wherein said active ingredient is 9-chloro- 2,3,4,5tetrahydro 1H 1,4 diazepino[l,2-a]indole hydrochloride.

10. Claim 6 wherein said active ingredient is 9-chloro- 2,3,4,5tetrahydro ll methyl lH-l,4diazepino[l,2- a] indole hydrochloride.

11. Claim 6 wherein said dosage unit is a tablet.

12. Claim 6 wherein said dosage unit is a capsule.

References Cited R. Chem. Abst. vol. 72 55528V (1970).

STANLEY J. FRIEDMAN, Primary Examiner UNITED STATES PATENT 0FCERTIFICATE OF CORRECTION Patent No. 3,7 7,577 Dated January 97 Inventor(s) Joseph Francis Gardocki It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

' In Column 6, Claim 6, Line after dosage unit, the phrase "formcomprisingper dosage unit", has been omitted."

Signed and sealed this 10th day of Septem-bef'l974.

(SEAL) Attest:

McCOY M. GIBSON, JR. C. MARSHALL DANN Commissioner ofPatents AttestingOfficer

